The natural hormone, 1α,25-dihydroxyvitamin D3 and its analog in the ergosterol series, i.e., 1α,25-dihydroxyvitamin D2, are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, various side chain homologated vitamins, and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
A new class of vitamin D analogs, i.e., the so called 19-nor-vitamin D compounds, are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D3) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity. Thus, these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders. Two different methods of synthesis of such 19-nor-vitamin D analogs have been described [Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 25(1991), and DeLuca et al., U.S. Pat. No. 5,086,191].
In U.S. Pat. No. 4,666,634, 2β-hydroxy and alkoxy (e.g., ED-71) analogs of 1α,25-dihydroxyvitamin D3 have been described and examined by Chugai group as potential drugs for osteoporosis and as anti-tumor agents. See also Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989). Other 2-substituted (with hydroxyalkyl, e.g., ED-120, and fluoroalkyl groups) A-ring analogs of 1α,25-dihydroxyvitamin D3 have also been prepared and tested [Miyamoto et al., Chem. Pharm. Bull. 41, 1111 (1993); Nishii et al., Osteoporosis Int. Suppl. 1, 190 (1993); Posner et al., J. Org. Chem. 59, 7855 (1994), and J. Org. Chem. 60, 4617 (1995)]. Recently, similar analogs of 1α,25-dihydroxy-19-nor-vitamin D3 have also been synthesized, i.e., compounds substituted at the 2-position with hydroxy or alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713), which exhibit interesting and selective activity profiles. All these studies indicate that binding sites in vitamin D receptors can accommodate different substituents at C-2 in the synthesized vitamin D analogs.
Recently, analogs which are characterized by the transposition of the ring A exocyclic methylene group, present in the normal vitamin D skeleton, from carbon 10 (C-10) to carbon 2 (C-2), i.e., 2-methylene-19-nor-vitamin D compounds, were synthesized and tested. Molecular mechanics studies indicate that such molecular modification does not substantially change the conformation of the cyclohexanediol ring A. However, introduction of the 2-methylene group into the 19-nor-vitamin D carbon skeleton changes the character of its (1α- and 3β-) A-ring hydroxyls. They are both now in the allylic positions, similarly, as 1α-hydroxyl group (crucial for biological activity) in the molecule of the natural hormone, 1α,25-(OH)2D3. These analogs exhibit similar rates of binding to the receptor as 1α,25-dihydroxyvitamin D3 and were also characterized by high cell differentiation activity. These compounds were characterized by little, if any, intestinal calcium transport activity, as compared to that of 1α,25-dihydroxyvitamin D3, while exhibiting relatively high activity, as compared to that of 1α,25-dihydroxyvitamin D3 in their ability to mobilize calcium from bone.
More than ten years ago, another interesting 1α,25-dihydroxyvitamin D2 analog was synthesized, namely, 1α,25-dihydroxy-24-epivitamin D2, which was essentially devoid of bone calcium mobilization but unexpectedly exhibited comparable binding to the receptor as 1α,25-dihydroxyvitamin D3 [DeLuca et al., U.S. Pat. No. 5,036,061]. Related patents referring to 1α,25-dihydroxy-24-epi-vitamin D2 include DeLuca et al., U.S. Pat. No. 4,769,181, DeLuca et al., U.S. Pat. No. 54,973,584, and DeLuca et al., U.S. Pat. No. 4,588,716. In a continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, a 19-nor-vitamin D analog, characterized by the presence of methylene substituent at the carbon 2 (C-2) and 24 R in the side chain, has now been synthesized and tested.